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  Method of inducing melanogenesis in humans with mc1r variant allelesUSPTO Application #: 20080004213Title: Method of inducing melanogenesis in humans with mc1r variant alleles Abstract: A method for inducing melanogenesis in a human subject having a melanocortin 1 receptor (MC1R) variant allele associated with loss of or diminished receptor function comprises administering to said subject an amount of an α-melanocyte stimulating hormone (α-MSH) analogue effective to induce melanogenesis by the melanocytes in the skin or other epidermal tissue of the subject. (end of abstract)
Agent: Greenlee Winner And Sullivan P C - Boulder, CO, US Inventor: Stuart Michael Humphrey USPTO Applicaton #: 20080004213 - Class: 514009000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai, Cyclopeptides The Patent Description & Claims data below is from USPTO Patent Application 20080004213. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The present invention relates broadly to a method of inducing melanogenesis in humans, that is stimulating the production of melanins by the pigment-producing cells (keratinocytes and/or melanocytes) of the skin, in particular in humans having a loss-of-function or diminished function mutation(s) in the melanocortin-1-receptor gene. BACKGROUND OF THE INVENTION [0002] Non-melanoma skin cancer (NMSC) is now the most common form of cancer in white populations and incidence rates for NMSC and malignant melanoma are increasing steadily world wide. While ultraviolet radiation (UVR) is the greatest environmental risk factor for skin cancer, skin pigmentation phenotype appears to be the most important genetic determinant of risk. [0003] The melanocortins include a family of peptide hormones that induce pigmentation by interaction with melanocortin 1 receptors (MC1R) in the epidermis (see Hadley, M E. The melanotropic hormones, In: Brake, D., editor. Endocrinology, 4.sup.th Edition, Simon & Schuster; 1982; pp. 153-76). The primary pigmentary hormone that is released from the pars intermedia of the pituitary gland in some non-human animals, and from UV-B exposed keratinocytes in human skin, is .alpha.-melanocyte stimulating hormone (.alpha.-MSH). This 13 amino acid peptide binds to MC1R to induce cyclic AMP-mediated signal transduction leading to the synthesis of melanin polymers from DOPA precursors. Two types of melanins can be expressed in humans. The brownish-black pigment eumelanin is believed to convey protection from sun damage, whereas the reddish, sulfur-containing pigment, phaeomelanin is often expressed in light-skinned human populations that report a poor tanning response to sunlight. These poorly-tanning, easily-burning populations, often possess defects in the MC1R gene [28], and are generally thought to be at a greater risk of developing both melanoma and non-melanoma skin cancers [5, 21]. [0004] .alpha.-MSH binds MC1R to stimulate both eumelanogenesis, by upregulating tyrosinase activity, and melanocyte proliferation, through activation of adenylate cyclase [1, 6, 13]. Eumelanin is known to have photoprotective properties as it is resistant to photodegradation and has the ability to quench reactive oxygen radicals [19, 20]. Studies investigating whether variant alleles affect the interaction between .alpha.-MSH, MC1R and the downstream processes have found that the MC1R gene is highly polymorphic and variants such as Arg151Cys, Arg160Trp and Asp294His, are associated with fair skin colour and red hair, characterised by a low melanin content and a low eumelanin to phaeomelanin ratio [5, 16, 28]. Several variants, including the above-mentioned, have since been associated with an increased risk of skin cancer independent of pigmentation phenotype [4, 17, 21]. It has also been demonstrated that the variants Arg142His, Arg151Cys, Arg160Trp and Asp294His are loss-of-function alleles, and one effect of having these variant alleles is a decrease in the binding affinity of MC1R to .alpha.-MSH [11, 15, 22, 24, 27]. Investigations conducted into human MC1R variants have established that either "loss-of-function" or "diminished function" mutations in the MC1R gene sensitise human melanocytes to the DNA damaging effects of UV radiation, which may increase skin cancer [12, 24, 25]. [0005] Although (.alpha.-MSH stimulates natural skin protection, the process requires harmful UVR. It has previously been disclosed that a super-potent derivative of .alpha.-MSH, Melanotan-1, (Nle.sup.4-D-Phe.sup.7-.alpha.-MSH), can induce tanning in human volunteers [18]. Melanotan (MT-1), contains two amino acid substitutions and exhibits a 10- to 100-fold increased activity in frog and lizard bioassays for pigmentation [25], increases melanogenesis and tyrosinase activity in human melanocytes, and more specifically, induces significant increases in the eumelanin content of melanocytes while having a lesser effect on the levels of phaeomelanin [7, 13, 14]. Several studies have assessed the pharmacokinetic and tanning effects of Melanotan in humans and found a significant increase in eumelanin, but not phaeomelanin, content in skin [7, 18]. Although melanotropins have been postulated to effect immunologic changes, all of the prior trials reported only minimal side effects such as facial flushing and transient GI upset, unless doses greater than those needed for tanning were administered. [0006] U.S. Pat. No. 4,457,864 (issued Jul. 3, 1984), discloses analogues of .alpha.-MSH, including Nle.sup.4-D-Phe7-.alpha.-MSH. Cyclic analogues of .alpha.-MSH are disclosed in U.S. Pat. No. 4,485,039 (issued Nov. 27, 1984). The use of these and other analogues of .alpha.-MSH for stimulating the production of melanin by integumental melanocytes is disclosed in Australian Patent No. 597630 (dated Jan. 23, 1987) and U.S. Pat. No. 4,866,038 (issued Sep. 12, 1989), U.S. Pat. No. 4,918,055 (issued Apr. 17, 1990) and U.S. Pat. No. 5,049,547 (issued Sep. 17, 1991). Australian Patent No. 618733 (dated May 20, 1988), and U.S. Pat. No. 5,674,839 (issued Oct. 7, 1997), U.S. Pat. No. 5,683,981 (issued Nov. 4, 1997) and U.S. Pat. No. 5,714,576 (issued Feb. 3, 1998) disclose further linear and cyclic .alpha.-MSH fragment analogues, and the use of these biologically-active analogues in stimulating melanocytes. The contents of all these published Australian and US patents are incorporated herein by reference. [0007] In work leading to the present invention, it has been demonstrated that notwithstanding the significantly reduced response to .alpha.-MSH of human melanocytes having either "loss-of-function" or "diminished function" mutations, Melanotan is effective in inducing melanogenesis in human subjects having MC1R variant alleles. In particular, it has been demonstrated that significant increases in melanin density can be induced in such subjects by use of Melanotan, in some cases leading to melanin density levels similar to the levels in subjects having the wild-type MC1R. [0008] Accordingly, the method of the present invention enables the induction of melanogenesis in human subjects having a "loss-of-function" or "diminished function" mutation(s) in the MC1R gene, leading to increased melanin density levels in these subjects and reduced risk of skin cancer. SUMMARY OF THE INVENTION [0009] Bibliographic details of the publications referred to in this specification by reference number are collected at the end of the specification. [0010] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. [0011] Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications, the invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. [0012] In one aspect, the present invention provides a method for inducing melanogenesis in a human subject having an MC1R variant allele associated with loss of or diminished receptor function, which comprises the step of administering to said subject an amount of an .alpha.-MSH analogue effective to induce melanogenesis by the melanocytes in the skin or other epidermal tissue of the subject. [0013] In another aspect, the present invention provides the use of an .alpha.-MSH analogue in the manufacture of a preparation for inducing melanogenesis in a human subject having an MC1R variant allele associated with loss of or diminished receptor function. BRIEF DESCRIPTION OF THE DRAWING [0014] FIG. 1 shows the association between maximum change in melanin density and baseline melanin density at the inner upper arm in intent-to-treat (ITT) individuals. DETAILED DESCRIPTION OF THE INVENTION [0015] .alpha.-MSH stimulation of the MC1 receptor following UV exposure is central to the tanning response in human melanocytes. One of the many effects of .alpha.-MSH is to increase the eumelanin: phaeomelanin ratio thereby increasing the photoprotective properties of the basal and suprabasal layers of the skin [2, 7]. The interaction between .alpha.-MSH and MC1R is affected by the presence of gene sequence variants in the receptor. Variation in the MC1R gene sequence is extremely common, for example, it has been shown that over 75% of the UK population harbour coding region variants [26] and in the present study 68% of a group of Australian volunteers had one or more variant alleles. Variations have been found in over 80% of individuals with red hair and/or fair skin that tan poorly but in fewer than 20% of individuals with brown or black hair and in less than 4% of those who showed a good tanning response [2, 3]. This suggests that in humans, as in other mammals, the MC1R is a key point in the regulation of pigmentation phenotype and, more importantly, that variations in this protein are associated with a poor tanning response. [0016] As described above, the present invention provides a method for inducing melanogenesis in a human subject having an MC1R variant allele associated with loss of or diminished receptor function, which comprises the step of administering to said subject an amount of an .alpha.-MSH analogue effective to induce melanogenesis by the melanocytes in the skin or other epidermal tissue of the subject. [0017] Human subjects having an MC1R variant allele associated with loss of or diminished receptor function, demonstrated by a reduced response to .alpha.-MSH, have a so-called "loss-of-function" or "diminished function" mutation in the MC1R gene. The melanocytes of such subjects may be either homozygous or heterozygous for such variations, and the loss of receptor function associated with the variation may vary from full to only partial loss of function. Those with a partial loss of function are referred to as "diminished function" alleles. Particular variant alleles which are relevant to the method of the present invention include, by way of example, Val60Leu (V60L), Asp84Glu (D84E), Val92Met (V92M), Arg142His (R142H), Arg151Cys (R151C), Arg160Trp (R160W), and Asp294His (D294H). The present invention extends to induction of melanogenesis in human subjects having one or more of these "loss-of-function" or "diminished function" MC1R variant alleles. [0018] In its broadest aspects, the present invention extends to the use of an .alpha.-MSH analogue. These analogues may be synthesised according to the procedures set out in the patent documents referred to herein, or according to methods used in preparing synthetic .alpha.-MSH which are well-known to persons skilled in this art. [0019] The term ".alpha.-MSH analogue" referred to herein is defined as a derivative of .alpha.-MSH which exhibits agonist activity for the melanocortin-1 receptor (MC1R), the receptor to which .alpha.-MSH binds to initiate the production of melanin within a melanocyte. Such derivatives include derivatives in which (i) one or more amino acid residues are deleted from the native .alpha.-MSH molecule at the N-terminal end, the C-terminal end, or both; and/or (ii) one or more amino acid residues of the native .alpha.-MSH molecule are replaced by another natural, non-natural or synthetic amino acid residue; and/or (iii) an intramolecular interaction forms as a cyclic derivative. Continue reading... Full patent description for Method of inducing melanogenesis in humans with mc1r variant alleles Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Method of inducing melanogenesis in humans with mc1r variant alleles patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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